Alemtuzumab is a humanized monoclonal antibody targeting CD52, a glycosylphosphatidylinositol-anchored surface antigen broadly expressed on lymphocytes and other immune cells. Although currently approved for multiple sclerosis and used in selected transplantation settings, alemtuzumab was among the earliest lymphocyte-depleting biologics explored across a wide spectrum of autoimmune rheumatic diseases. With renewed interest in deep immune-depleting strategies, including CAR-T cells and bispecific T-cell engagers, revisiting the immunobiology and clinical experience of alemtuzumab is timely. This review summarizes current knowledge of CD52 structure, expression, and immunological function, highlighting its dual role as both a co-stimulatory and immunoregulatory molecule. We examine the mechanisms underlying alemtuzumab-induced lymphocyte depletion, subsequent immune reconstitution, and the paradoxical development of secondary autoimmunity. Clinical evidence for alemtuzumab use in rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, idiopathic inflammatory myopathies, ocular inflammatory disease, and Behçet's syndrome, is reviewed, with emphasis on efficacy, durability of response, and safety outcomes. Across multiple refractory disease settings, alemtuzumab has demonstrated the capacity to induce rapid clinical improvement and, in some cases, prolonged drug-free remission. However, treatment is limited by risks of infection, delayed immune reconstitution, and immune dysregulation. We conclude that alemtuzumab remains a potent immunomodulatory option in selected refractory rheumatic diseases, provided that careful patient selection, cautious monitoring, and long-term follow-up are implemented.

Objectives This article aimed to articulate the most important unmet scientific needs in rheumatology. Methods At the 25th Advances in Targeted Therapies (ATT) meeting, over 100 investigators joined 6 disease-focused breakout groups (rheumatoid arthritis [RA], psoriatic arthritis [PsA], axial spondyloarthritis [axSpA], systemic lupus erythematous [SLE], systemic sclerosis [SSc], and osteoarthritis [OA]). Each group, led by a facilitator and rapporteur, mapped (i) key unmet needs, (ii) promising mechanistic or therapeutic approaches, and (iii) near-term priorities for research and trials. This report synthesises the consensus highlights. Results Six disease-focused groups (RA, PsA, axSpA, SLE, SSc, and OA) identified convergent priorities: earlier detection and interception; validated molecular and clinical endotypes to guide therapy; strategies for immune reset and short-course induction combinations with strict safety oversight; metabolic modifiers; precision targets in axSpA and fibroblast-directed approaches in RA; phenotype-driven therapeutic development and intra-articular options in OA; and pragmatic trial designs that include pregnant persons and very early disease. Conclusions Across immune-mediated diseases, progress will hinge on validated endotypes, practical interception strategies, and trials that reflect real-world populations. The immediate agenda is to de-risk immune reset and induction approaches, standardise tissue and digital biomarkers, and close evidence gaps for refractory disease. Prevention—and ultimately cure—remains the horizon.

OBJECTIVES:In our previously reported trial of intra-articular tolerogenic dendritic cells (tolDC) as a treatment to restore immune tolerance in autoimmune arthritis, high doses of cells appeared to stabilise knee symptoms, although no systemic clinical or immunomodulatory effects were observed. We therefore sought to understand how tolDC affected the local synovial immune landscape. METHODS:Synovial biopsies were taken at baseline and 14 days after intra-articular injection of tolDC or, as a control, saline washout. Histopathological analyses (Krenn evaluation and pathotype) and multiparametric imaging mass cytometry (IMC) were performed on paired synovial tissues from 7 participants (5 tolDC-treated and 2 controls), selected based on tissue availability at both time points. The IMC panel included 27 antibodies defining lymphoid, myeloid, and stromal cells. RESULTS:We observed no changes in the histopathology or the overall distribution of broadly classified cell populations (myeloid, lymphoid, and stromal) before and after tolDC administration. Furthermore, the proportions of CD4+ and CD8+ T cells were not altered, with no indication that tolDC had induced regulatory T cells within the synovium. However, we found a significant increase in a subset of myeloid cells expressing high levels of the inflammation resolution marker Mer tyrosine kinase (MerTKHigh), which positively correlated with tolDC dose. Moreover, the percentages of total MerTK+ myeloid cells inversely correlated with arthroscopic synovitis scores at both time points. CONCLUSIONS:The tolDC-induced increase in synovial Myeloid MerTKHigh cells may have local immune modulatory effects and provide promising evidence for an effect of tolDC treatment on the synovial immune landscape.

Abstract FcγRIIa, encoded by FCGR2A , is a widely expressed Fc receptor implicated in autoimmunity and infectious disease susceptibility. To fine-map the rheumatoid arthritis (RA) association at the complex FCGR locus, we combined gene-specific resequencing, genetic association studies in UK and Spanish European cohorts, functional genomics, structural biology, biophysical analyses, and cellular assays. We identified a common European FCGR2A haplotype (2A.3), defined by Q27W, H131H, and the RA-associated SNP rs12746613, which showed the strongest association with RA. Multi-omics analyses demonstrated that 2A.3 is associated with reduced expression of the soluble FCGR2A splice variant and lower circulating soluble FcγRIIa levels. Functional studies revealed altered IgG interactions and delayed FcγRIIa signal transduction associated with Q27W, while structural analyses found no evidence for stable ectodomain dimerisation. Together, these findings identify 2A.3 as an important functional contributor to RA susceptibility and provide mechanistic insight into how FCGR2A variation may influence immune regulation and disease risk in Europeans.

BACKGROUND:Clinical trials aimed at preventing rheumatoid arthritis in individuals at risk have had variable results. The long-term outcomes of disease interception, however, are not known. We aimed to examine the long-term effect of therapeutic intervention, with emphasis on efficacy and safety. METHODS:The Arthritis Prevention In the Preclinical Phase of Rheumatoid arthritis with Abatacept (APIPPRA) phase 2b, randomised controlled trial recruited 213 anti-citrullinated protein antibody (ACPA) positive individuals with arthralgia in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands, randomly assigning participants to 52 weekly subcutaneous injections of 125 mg abatacept (n=110) or placebo (n=103), with another 52 weeks of follow-up. The APIPPRA Long-Term Outcome (ALTO) study extended follow-up for between 4 and 8 years and study participants and clinical assessors remained masked to treatment group. The primary outcome was the time from randomisation to development of clinical synovitis in at least three joints, rheumatoid arthritis according to American College of Rheumatology-European Alliance of Associations for Rheumatology 2010 criteria, or first treatment with disease modifying anti-rheumatic drugs, whichever was met first. The primary outcome was also stratified by autoantibody profiles defined at the time of randomisation. People with lived experience of rheumatoid arthritis had input into the APIPPRA study design. The study was registered at ISRCTN (ISRCTN-12680338), and is completed. FINDINGS:Between April 26, 2021, and Jan 31, 2023, 143 APIPPRA study participants enrolled in ALTO: 71 in the abatacept group and 72 in the placebo group (mean age 48·2 years [SD 11·2], 112 [78%] females, 31 [22%] males, 116 [81%] White). Median follow-up time from randomisation was 55 months (IQR 23-74). Primary events increased by 54 to 119. The initial between-group difference in restricted mean arthritis-free survival time observed at 2 years in APIPPRA remained significant at 4 years (4·9 months 95% CI 0·1-9·6; p=0·044), although the magnitude of this difference diminished over time. Assessments of disease activity and patient reported outcomes revealed no significant differences between groups beyond the treatment period. However, although participants with a broad autoantibody profile at baseline were at highest risk of progressing, this subgroup responded better to abatacept. There were 18 serious adverse events in the abatacept group and 13 in the placebo group; none deemed related to study drug. INTERPRETATION:In this at-risk population, 1-year treatment with abatacept delayed progression to rheumatoid arthritis for up to 4 years. Those at highest risk of progression have a broad autoantibody profile but are more responsive to abatacept treatment. FUNDING:Bristol Myers Squibb.

OBJECTIVE:CD4 T cells specific for citrullinated (cit) peptides are key players in rheumatoid arthritis (RA) immunopathogenesis. Characterizing these cells and identifying features of healthy and RA-associated autoreactivity will provide valuable insight into disease mechanisms and form the basis of immune state biomarkers to facilitate the next generation of RA treatments. We sought to characterize these cells in a UK early arthritis cohort. METHODS:Cit-peptide-specific (autoreactive) CD4 T cells from human leukocyte antigen (HLA)-DRB1 04:01-positive healthy controls (HCs; n = 9), patients with RA at different disease stages (n = 17 pretreatment and 13 receiving treatment), and six at-risk individuals were assessed using major histocompatibility complex II peptide tetramers combined with spectral flow cytometry. Autoreactive T cell frequency and phenotype were studied, with a particular focus on the memory CD4 T cell compartment. RESULTS:There was no statistically significant difference in autoreactive T cell frequency between comparator groups. In HCs, however, autoreactive T cells were more likely to be naive. In early pretreatment RA, autoreactive memory T cells demonstrated down-regulation of CD27 and CD28 and expression of the fractalkine receptor CX3CR1, features that have been linked to CD4 cytotoxicity. The proportion of CD27-negative autoreactive cells decreased following treatment, and RA-associated features were evident in some at-risk donors before RA onset. CONCLUSION:In RA, CD4 T cell autoreactivity is characterized by a surface phenotype that suggests in vivo activation and the potential to acquire cytotoxic capacity, whereas healthy autoreactivity demonstrates naivety. These observations suggest maturing autoreactivity in RA and may provide novel tools for monitoring disease progression and tolerance.

Background The aim of this systematic review and meta-analysis was to examine autoantibody positive individuals and define: (a) the relative risk of rheumatoid arthritis (RA) compared with autoantibody negative individuals and (b) the cumulative incidence of RA over time, in different populations.Methods A systematic literature search was performed in August 2025. Retrospective case control studies of individuals with RA and healthy matched controls were identified and relative risk of RA was calculated. Prospective observational studies or randomised controlled trials of autoantibody positive individuals were identified and pooled survival models were used to estimate cumulative incidence of progression to arthritis.Results 293 full-text articles fulfilled screening criteria and 26 were eligible for meta-analysis. The presence of serum autoantibodies confers between a 3.1--19.3-fold increase risk of developing RA. Prospective studies of anticyclic citrullinated peptide 2 (CCP2) or CCP3 positive individuals were grouped according to additional criteria; presence of arthralgia, presence/absence of immunoglobulin M rheumatoid factor (IgM-RF) and first-degree or second-degree relatives with RA. The estimated cumulative incidence of RA at 12 months was highest for CCP2 positive individuals with arthralgia and IgM-RF, at 35.2% (95% CI 29.3% to 41.2%).Conclusion A considerable number of autoantibodies have been examined as predictors for RA; however, the fastest rate of progression to RA in this study occurred in those with CCP2 and IgM-RF in combination with arthralgia. Importantly, the risk of developing RA changes over time for individuals with arthralgia, and they are at the highest risk of progression within the first 24 months of follow-up.PROSPERO registration number CRD42021231245.

BackgroundPatients with immune-mediated inflammatory disease (IMID), including autoimmunity, fared substantially worse than the general population during the COVID-19 pandemic, both in terms of infection outcomes and disruption to daily life. Despite this, COVID-19 vaccine uptake has not been universal in this population. The absence of patients with IMID from clinical trials and the subsequent lack of precision in vaccine safety profiling have resulted in vaccine hesitancy in this high-risk group. ObjectiveThis protocol sets out an investigation that aims to address this by enhancing COVID-19 vaccine pharmacovigilance for patients with IMID. Combining the international data and knowledge assets of the COVID-19 Vaccination in Autoimmune Diseases (COVAD) 1 study and the electronic Delphi Study to Define and Risk-Stratify Immunosuppression (DESTINIES), the objective is to differentiate patient-reported COVID-19 infection and vaccine outcomes between participants with systemic, single organ, and overlap IMID and general population controls. MethodsThe COVAD-1 study successfully collected anonymized data on the demographic, health, COVID-19 infection, and COVID-19 vaccination outcomes of a broad range of participants with IMID between March and December 2021. This protocol expands on this initial analysis by using IMID specialists within the DESTINIES Consortium to allocate survey respondents into single organ and systemic categories and thereby produce comparative vaccine benefit-risk profiles between these and general population controls. Because of the respondents’ ability to self-report multiple diagnoses, an overlap group was introduced for those affected by both single organ and systemic disease. Descriptive statistics and both single and multivariable logistic regressions will be used to test for significant differences in COVID-19 infection rates, severity, duration, and vaccine side effects between these study groups and general population controls. ResultsA panel of 7 IMID experts successfully allocated COVAD-1 diagnoses into single organ and systemic categories; this also directed overlap category membership. Although this work is preliminary and highly exploratory, we anticipate that subsequent analysis will reveal disproportionate levels of severe COVID-19 infection outcomes (hospitalization with and without oxygen support) and vaccine side effects (mild and major) among participants with systemic manifestations of IMID, especially those that qualify for the overlap IMID category. ConclusionsAdvocating for direct-to-patient vaccine reporting pathways, this study intends to produce more precise vaccine safety profiles of patients with IMID. It seeks to resolve current gaps in pharmacovigilance and potentially remedy vaccine hesitancy in high-risk groups by doing so. The international nature of COVAD-1 data collection and the nuance of information made available through participant self-report are to the advantage of this protocol. However, the dependence of this study on participant recall, the small sample sizes handled, and the questionable relevance of these data in the contemporary Omicron era are to the detriment of this work. International Registered Report Identifier (IRRID)DERR1-10.2196/68785

Objectives: Patients with rheumatoid arthritis (RA) display different trajectories towards improvement of disease. We aimed to disentangle the heterogeneity of RA disease trajectories from the first clinical visit onwards using graph-based pseudotime analysis. Methods: We studied early patients with RA over 1.5 years in 2 data sets: Leiden (Netherlands), n = 1237, with 5017 visits, and Towards a Cure for Early Rheumatoid Arthritis (TACERA) (United Kingdom), n = 243, with 750 visits. We created a pipeline for time-independent clustering of clinical and haematologic features to identify disease states. Sequence analyses of these states defined the trajectories. We studied the predictability of the trajectories with baseline features. Results: Clustering identified 8 disease states with localised inflammation (joints) and systemic inflammation (erythrocyte sedimentation rate [ESR] or leucocytes) as the main discriminating factors. The disease state sequences consisted of 4 trajectories, which we independently replicated in TACERA: A, high ESR; B, rapid progression from many inflamed joints towards remission; C, high leucocytes; and D, many inflamed joints with poor prognosis. Systemic vs local inflammation patterns showed moderate predictability at baseline (sensitivity of 71% and precision of 0.73 for trajectory A, although lower precision of 0.52 for trajectory B), while other trajectories were less predictable. Trajectories C and D had strong resemblance with B at baseline but deteriorated into less favourable trajectories. Patients in trajectory A were more often female and on average older. The trajectories were not explained by time till disease-modifying anti-rheumatic drug, baseline disease activity, or symptom duration. The suboptimal trajectories coincided with worse patient-reported outcomes, even when the inflammation was mainly systemic. Conclusions: We identified 4 distinct trajectories in early RA, differentiating RA into localised vs systemic inflammation. Our results highlight potential differences in disease pathology and opportunities for further targeted treatment. Inevitably, patterns without linkage to our selected features could not be detected.

OBJECTIVES:The Advances in Targeted Therapies annual meeting brings together experts within the field of rheumatology and immunology to highlight and discuss the latest scientific developments and needs in the field. The objective is to highlight unmet scientific needs in the field of rheumatology. METHODS:The 24th annual Advances in Targeted Therapies meeting convened with more than 100 international clinicians and scientific researchers in rheumatology, immunology, and other specialities relating to all aspects of immune-mediated inflammatory diseases. During the meeting, we held 5 rheumatologic disease-specific discussion sections consisting of experts in each field. These groups included rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), osteoarthritis (OA), and systemic lupus erythematosus (SLE). In each group, experts were asked to identify the top 2 to 3 most important overarching and disease-specific scientific unmet needs to be addressed in the next 5 years. RESULTS:The overarching themes across disciplines included the need for precision medicine, improved classification of disease states, and the further identification of targets and associated therapies, including the potential role of chimeric antigen receptor (CAR) T cell therapies. Within RA, the group highlighted the lack of precision medicine and the need for better biomarkers. Further, the lack of targeted therapies against fibroblasts in RA was discussed, with the potential impact of targeting fibroblasts early in the disease as an unmet need. For PsA, there is a continued need for a better definition of disease endotypes and for the categorisation of those with complex and difficult-to-treat (D2T) diseases. The development of bispecific molecules and combination therapeutic approaches remain a high priority. For axSpA, the disease-modifying characteristics of nonsteroid anti-inflammatory drugs need further evaluation, as does the treatment of residual pain and fatigue frequently in the disease. In OA, new therapeutic targets remain an unmet need, and the discussion group prioritised potential experimental strategies that could lead to innovative therapeutic targets. Elucidating the specific signalling and target cells responsible for, or inhibiting, repair will be essential for developing targeted therapies. SLE experts emphasised the need to identify the most predictive biological contributions to disease progression in patients with early clinical precursors of SLE. The role of CAR T cell therapy must be further investigated, along with ancillary biologic studies (eg, immune system profiling) that provide critical insights into disease pathogenesis. Further, there is a need to determine the relationship of patient-relevant symptoms to the pathophysiology of SLE and identify new therapeutic targets for these symptoms. CONCLUSIONS:There remain many unmet needs on the road to precision medicine with regard to identifying disease endotypes and biomarkers for disease progression or therapeutic response. For most diseases discussed, a strong unmet need remains with regard to identifying new targets and therapies for those with refractory or D2T disease. The ability to prevent or cure rheumatic disease remains the ultimate unmet need in rheumatology.

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein that plays a key role in signalling pathways downstream of diverse surface receptors in B-cells and myeloid cells. These include the B-cell receptor itself, Fc receptors including FcεRI, toll-like receptors and chemokine receptors. Congenital deficiency of BTK causes X-linked agammaglobulinaemia because of B-cell developmental block, and BTK inhibitors (BTKi) are approved for the treatment of certain B-cell malignancies. They have also been studied in a variety of autoimmune and inflammatory diseases. In rheumatic conditions, results have been disappointing in rheumatoid arthritis (RA) and systemic lupus erythematosus but with some evidence for efficacy in Sjogren's syndrome. Data are more positive in multiple sclerosis, as well as in the cutaneous disease chronic spontaneous urticaria and possibly pemphigus vulgaris. BTKi may also find a role in severe allergic disease such as food allergy. First generation BTKi had a safety profile that included cardiotoxicity, hypertension, haemorrhage and rash. Second generation inhibitors have a more acceptable safety profile although dose-limiting toxicity is still observed in some conditions, including RA. Pharmacokinetic factors aside, the variable efficacy in different diseases is not fully explained but is likely to reflect disease dependence on different pathways in B-cells and myeloid cells and their relative sensitivity to BTKi.

Background:The lack of international consensus on defining and categorising immunosuppression has undermined disease surveillance and patient care, particularly during the COVID-19 pandemic. To address this, a global expert panel was recruited to join the eDElphi STudy to fully defiINe and COVID-risk stratify ImmunosupprESsion (DESTINIES) and develop a COVID risk-stratified digital phenotype for 'adult immunosuppression' (the DESTINIES phenotype). Methods:Panellists were presented with all medical diagnoses and procedures cited in prevailing immunosuppressed definitions; they evaluated their appropriateness for the DESTINIES phenotype and their risks for severe COVID-19 outcomes through anonymous online questionnaires and discussion. Panel agreement with a series of clinical statements were also assessed; statements incorporated longstanding disputes, including variables that could reverse immunosuppression. Each round of data collection informed and refined a draft phenotype until final ratification. This study was active between May and September 2024. Findings:Sixty-four experts from four continents and 12 international agencies completed two rounds of consensus questionnaire, a discussion group and ratifying vote. Panellists identified candidates posing higher (e.g. Transplantation, Primary Immunodeficiency) and lower COVID-19 risk (e.g. Anorexia nervosa, Cerebral spinal fluid leak) but disagreed on the categorisation of others (e.g. Asplenia, Immune-mediated Inflammatory Disease). Consensus was reached on ten clinical statements, notably removing Drug-managed HIV and Cancer remission from consideration as immunosuppressed. The DESTINIES phenotype was ratified with near unanimous support (94%) for implementation in surveillance. Interpretation:Pending validation, the DESTINIES phenotype provides a clinically meaningful, internationally ratified and digitally practical method for identifying and COVID-19 risk-stratifying adult immunosuppressed patients in healthcare data. Funding:This work was funded by the UK Medical Research Council and EMIS Health.

Transparent and accurate reporting in early phase dose-finding (EPDF) clinical trials is crucial for informing subsequent larger trials. The SPIRIT statement, designed for trial protocol content, does not adequately cover the distinctive features of EPDF trials. Recent findings indicate that the protocol contents in past EPDF trials frequently lacked completeness and clarity. To address this gap, the international consensus-driven SPIRIT-DEFINE checklist was developed through a robust methodological framework for guideline development, with the aim to improve completeness and clarity in EPDF trial protocols. The checklist builds on the SPIRIT statement, adding 17 new items and modifying 15 existing ones.The SPIRIT-DEFINE explanation and elaboration (E&E) document provides comprehensive information to enhance understanding and usability of the SPIRIT-DEFINE checklist when writing an EPDF trial protocol. Each new or modified checklist item is accompanied by a detailed description, its rationale with supportive evidence, and examples of good reporting curated from EPDF trial protocols covering a range of therapeutic areas and interventions. We recommend utilising this paper alongside the SPIRIT statement, and any relevant extensions, to enhance the development and review of EPDF trial protocols.By facilitating adoption of the SPIRIT-DEFINE statement for EPDF trials, this E&E document can promote enhancement of methodological rigour, patient safety, transparency, and facilitate the generation of high-quality, reproducible evidence that will strengthen the foundation of early phase research and ultimately improve patient outcomes. Funding This work is a further extension of the SPIRIT-DEFINE study, which obtained no external funding. The principal investigator (CY) used internal staff resources, together with additional resources from external partners, to conduct this study. The SPIRIT-DEFINE study is a component of the DEFINE project, which also developed the MRC/NIHR funded CONSORT-DEFINE guidance. ICR-CTSU receives programmatic infrastructure funding from Cancer Research UK (C1491/A25351; CTUQQR-Dec22/100004), which has contributed to accelerating the advancement and successful completion of this work.

Abstract Background Rituximab is a chimeric monoclonal anti-CD20 antibody, used in the management of autoimmunity. It is known to have a favourable safety profile, however, a rare complication includes early-onset neutropenia (EON), defined as neutropenia having occurred within four weeks of rituximab treatment. Only eight case reports have been published so far, the majority of which relate to its use in SLE and none in rheumatoid arthritis (RA). We report here the first dedicated case series of post-rituximab EON in RA. Methods We identified 4 RA patients with EON. All were anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) positive. Demographics were female:male ratio 3:1, with mean age 58 (range 33-69). Our first patient (65F) had a past medical history (PMH) of asymptomatic primary biliary cirrhosis (ANA+ve, AMA+ve, M2+ve), the second (65F) had Sjogren’s syndrome (ANA+ve, dsDNA+ve, IgG+ve) and the third (69F) had diverticulosis, Raynaud’s phenomenon and subacute cutaneous lupus with no systemic manifestations (ANA+ve, Ro and La +ve). The fourth patient (33M) had no PMH. Three had previously reported intermittent neutropenia on prior disease modifying anti-rheumatic drug (DMARD) therapy, but none were on DMARDs/doses known to cause this at the time of Rituximab. Standard Rituximab regimens were administered (1g with 100mg IV methylprednisolone, two weeks apart) with two patients (33M, 69F) on concurrent methotrexate (15mg) and hydroxychloroquine (200mg) respectively. Results EON occurred at 4, 11 and 14 days (n = 2) (mean 10 days) post-infusion with mean nadir 0.57x109/L (range 0.05 - 1.17x109/L). It was the first treatment cycle for two patients (65F and 33M), whilst the others (65F and 69F) had received 2-3 previous cycles uneventfully. Patient 2, 65F and ANA+ve, subsequently developed neutropenic sepsis and was treated with standard protocol and G-CSF (granulocyte-colony stimulating factor). Cultures were negative and other investigations did not identify any infective source. The other three patients’ (33M, 69F) neutropenia resolved spontaneously without required intervention. Conclusion EON is a rare but serious complication of rituximab but to date no clear mechanism has been identified. It has been suggested that EON may be due to a bystander effect of lysozyme and granzyme release, secondary to B cell killing and that individuals with a high-affinity FcγRIIIa 158 V allele are more susceptible to this mechanism and therefore prone to a greater depth of neutropenia. Because of its relative acute onset, we may actually be under-recognising uncomplicated episodes of EON due to variability in routine blood monitoring post-treatment. We therefore want to highlight the need for vigilance in this patient cohort, particularly in those who are already susceptible to drug-induced neutropenia or are ANA+ve, in addition to vigilance irrespective of cycle number. Future monitoring of early neutrophil counts in Rituximab-treated RA patients may provide additional insight into this rare complication. Disclosures C. Lin None. A.R. Lorenzi None. F.A.H. Cooles None.

Regulatory T cells (Tregs) are immune regulatory T cells that are vital for controlling inflammation. The role of Tregs in inflammatory diseases namely psoriatic arthritis (PsA) is still poorly understood. The underlying reason being a lack of robust unbiased analysis to test the immune regulatory phenotype of human Tregs. Here, we propose that checkpoint receptors can identify functional Tregs in PsA. Using unbiased BD Rhapsody single-cell analysis, we have analyzed the expression pattern of checkpoint receptors in Tregs and found that PsA Tregs are enriched in the expression of CTLA4, TIGIT, PD-1, and GITR while TIM3 was downregulated. Furthermore, PD-1+ Tregs in PsA had an increased type 1 phenotype and expressed the protease asparaginyl endopeptidase. By harnessing the PD-1 signaling pathway and inhibiting asparaginyl endopeptidase, PsA Treg function was significantly enhanced in in vitro suppressor assays. Next, we interrogated the cell interaction pathways of Tregs in PsA and found a diminished crosstalk with circulating osteoclast precursors through the CD244-CD48 coreceptor pathways. Therapeutically, PsA Treg function could be enhanced by modulating PD1 and osteoclast interactions. Our study suggests that unconventional immune cell crosstalk with Tregs is severely diminished in PsA.